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The amino terminal lectin-like domain of thrombomodulin is required for
constitutive endocytosis
EM Conway, S Pollefeyt, D Collen and M Steiner-Mosonyi
Department of Medicine, University of Toronto, Ontario, Canada.
Thrombomodulin (TM) is a multidomain protein that serves as a cofactor in a
major natural anticoagulant system. To further characterize the
structure-function of TM, we have transfected COS cells with different
truncated forms of TM. In the first form, COS cells expressing TM that
lacks the putative signal peptide (17 residues); the lectin-like,
hydrophobic N-terminal domain (226 residues); and 12 residues of the first
epidermal growth factor (EGF)-like repeat (COSdel.238 cells) were found to
function normally with respect to TM transport to the cell surface and
thrombin-dependent protein C activation. However, in contrast to wild-type
TM, as visually studied by immunofluorescence and immunogold electron
microscopy, the COSdel.238 cells did not constitutively internalize
anti-TM-TM or thrombin-TM complexes. To identify the region responsible for
mediating the endocytic process, deletant forms of TM lacking either the
lectin-like region (residues 2- 155) or the hydrophobic region of the
N-terminal domain (residues 161- 202) were expressed in COS cells
(COSdel.2-155 and COSdel.161-202, respectively). Protein C cofactor
activity was maintained in both cells. Although the COSdel.161-202 cells
behaved similarly to wild-type TM-transfected cells, visual studies showed
a lack of constitutive internalization of thrombin-TM or anti-TM-TM
complexes in the COSdel.2- 155 cells. We conclude that the lectin-like
domain of human TM serves to regulate cell surface expression of TM via the
endocytic route and therefore may also play a major physiologic role in
controlling intracellular and extracellular accumulation of thrombin in a
variety of biologic systems.
Volume 89,
Issue 2,
pp. 652-661,
01/15/1997
Copyright © 1997 by The American Society of Hematology
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